Mechanisms for extending lifespan
(SENS): genetic aspectsAubrey D.N.J. de Grey
Department of Genetics, University of Cambridge
Email: [email protected]
Reprints, general info: http://www.gen.cam.ac.uk/sens/
“Is he nuts?”http://
www.technologyreview.com/articles/05/02/issue/mag_toc.asp
Aging in a nutshellMetabolism (the hugely messy network of homeostatic processes that keep us alive)
causes
Pathology (the hugely messy network of anti-homeostatic processes that kill us)
This is not controversial -- indeed, it is why most biogerontologists think there’s
little hope of curing aging for ages
Paradigms for intervention
Gerontology Geriatrics
Metabolism Pathology
An oft-neglected observationAging is indisputably a side-effect of essential
biochemical and cellular processesBUT
Its functional effect (loss of performance) is delayed
Putting it another way:
Being alive must have immediate side-effects, since metabolically active molecules are short-lived
BUTThose effects must accumulate, and have a
threshold level below which they are harmless
Aging in slightly less of a nutshell
Metabolism ongoingly causes “damage”
whereas
Damage only eventually causes pathology
This turns out to be very useful
Paradigms for intervention
Gerontology Geriatrics
Metabolism Damage Pathology
Paradigms for intervention
Gerontology Engineering Geriatrics
Metabolism Damage Pathology
Claim: unlike the others, the engineering approach can achieve a large extension of
human healthy lifespaspan quite soon
Metabolism Damage Pathology:
The seven deadly thingsRespiration (oxidation)
Carbohydrate metabolism (glycation)
Cell turnover (mutations,
telomere
shortening,
dysregulation,
stem cell
depletion)
Etc, etc, etc
Cell loss/atrophy
Protein crosslinks
Extracellular junk
Death-resistant cells
mtDNA mutations
Lysosomal junk
Nuclear [epi]mut’ns
Er.... that’s it!
Neurodegeneration
Atherosclerosis
Cancer
Diabetes
Hormone decline
Blindness
Immune decline
Etc, etc, etc
FAQ #1:
How do you know that this list is complete?
20 years is a suspiciously long time to find nothing out
Damage rising with age Proposed as contributing to aging by
Cell loss, cell atrophy Brody (1955) or earlier
Extracellular junk Alzheimer (1907)
Extracellular crosslinks Monnier and Cerami (1981)
Cell senescence Hayflick (1965)
Mitochondrial mutations Harman (1972)
Lysosomal junk Strehler (1959) or earlierNuclear [epi]mutations (only cancer matters) Szilard (1959) and Cutler (1982)
FAQ #2:
OK… How close are we to fixing these things?
Damage rising with age It or its effects reversible by
Cell loss, cell atrophy Exercise, cell therapy, growth factors
Extracellular junk Phagocytosis by immune stimulation
Extracellular crosslinks AGE-breaking molecules/enzymes
Death-resistant cells Cell ablation, reprogramming
Mitochondrial mutations Allotopic expression of 13 proteins
Lysosomal junk Transgenic microbial hydrolasesNuclear [epi]mutations (only cancer matters)
WILT: Telomerase/ALT knockout plus periodic stem cell reseeding
We know how to fix all of them (in mice, in principle!)
See www.gen.cam.ac.uk/sens/ for detail (lots of it, including all my publications)
Damage rising with age It or its effects reversible by
Cell loss, cell atrophy Exercise, cell therapy, growth factors
Extracellular junk Phagocytosis by immune stimulation
Extracellular crosslinks AGE-breaking molecules/enzymes
Death-resistant cells Cell ablation, reprogramming
Mitochondrial mutations Allotopic expression of 13 proteins
Lysosomal junk Transgenic microbial hydrolasesNuclear [epi]mutations (only cancer matters)
WILT: Telomerase/ALT knockoutplus periodic stem cell reseeding
We know how to fix all of them (in mice, in principle!)
See www.gen.cam.ac.uk/sens/ for detail (lots of it, including all my publications)
SENS components cover the genetic bases (no pun intended…)
Allotopic expression: insert many genes
Xenohydrolases: insert foreign genes
WILT: target genes, in vitro and in vivo
Q: How could these therapies ever undergo clinical trials?!
Q: How could these therapies ever undergo clinical trials?!
A: Robust Mouse Rejuvenation
Definition of RMR: trebling of the remaining lifespan of a cohort of 2yo mice that normally die at 3yo
Q: what’s so important about mice?
A: the other milestones1)Robust Mouse Rejuvenation - proves
plausibility of:
2)Robust Human Rejuvenation - give 30 extra healthy years to 55yo’s
3)Longevity Escape Velocity - indefinite youth
Indefinite youth????!!!!
Gerontology Engineering Geriatrics
Metabolism Damage Pathology
Damage can be kept sub-pathogenic indefinitely by repair that only
asymptotically approaches perfection
Longevity escape velocity
Conclusion: RHR gives LEV. The first 1000-year-old is probably only ~10 years
younger than the first 150-year-old
RMR’s probable impact on clinical trial policy
- Timeframe: I predict RMR will be achieved within 10 years
- How achieved: I predict all 7 SENS strands will be necessary for RMR or seen by then to be necessary for RHR
- Moreover: not just necessary, but sufficient
- Consequence: global “War On Aging”
War on Aging?- The “War on Cancer” was a misnomer:
- limited life-extension if successful- economically imperceptible to voters
- RMR will make RHR unarguably feasible- RHR should give longevity escape velocity
- indefinite youth- huge economic impact will be accepted
My inference: public (hence political) response to RMR will be unlike any previous biomedical situation, and more like wartime
